Aldosterone, a physiological mineralocorticoid, regulates sodium transport in epithelial tissues, particularly the distal nephron and colon. The response to aldosterone is mediated by a nuclear receptor, the mineralocorticoid receptor (MR; NR3C2) and involves non-genomic as well as genomic effects. The pivotal role of the MR in the mineralocorticoid response is demonstrated in MR null mice; these mice exhibit profound mineralocorticoid-unresponsive salt-wasting, which is inevitably fatal in the early neonatal period. Compromised mineralocorticoid action is associated with salt balance disorders and hyperaldosteroidism is associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. MR antagonism is coupled to reduced oxidative stress in endothelium and hence improved vascular function.
High levels of circulating aldosterone are associated with endothelial dysfunction in hypertensives and patients with congestive heart failure, effects that are principally mediated by the mineralocorticoid receptor. Prolonged hyperaldosteronism is also associated with kidney fibrosis and eventually failure (Trends Endocrinol Metab. 2008, 19(3)), 88-90). Blockade of MR in heart failure studies led to substantial reductions in mortality and morbidity, despite dosing being limited by MR mediated hyperkalemia (N. Engl. J. Med. 1999, 341(10), 709-17). Limited clinical trials have demonstrated beneficial effects of MR antagonists also in treatment of kidney disease including diabetic nephropathy (Kidney International 2011, 79, 1051). However, the risk for hyperkalemia is currently limiting the use of MR antagonists and particularly excludes diabetic patients. Novel, potent and selective MR antagonists should increase this therapeutic window between endothelial improvements and hyperkalemia of epithelial origin.    Non-steroidal MR antagonists disclosed in Bioorg. Med. Chem. Lett. 2005, 15, 2553 describe optimisation of 3,3-bisaryloxindoles as MR antagonists for use to treat congestive heart failure.    WO 2006/015259 relates to benzoxazinones as potent modulators of steroid hormone receptors including MR to treat a variety of disorders affecting the heart, kidney and the vasculature.    Opin. Ther. Pat. 2007, 17, 17 review the field of MR antagonists. The review also includes the two key steroidal MR antagonists eplerenone and spironolactone.    Expert Opin. Ther. Patents 2014, 24(2), 177 reviews the field of MR modulator in a patent review covering applications filed 2007-2012.    WO 2007/077961 relates to fused heterocyclic compounds as MR antagonists for treatment of hypertension, cardiac failure and the like.    DE 10 2007 009 494 disclose 4-aryl-1,4-dihydro-1,6-naphthyridin-3-carboxamides as MR antagonists for treatment of hypertension, heart failure, kidney disease and other conditions.    WO 2007/089034 disclose bicyclic compounds, such as N-(2,2-dimethyl-3-oxo-4-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methanesulfonamide, as binders to MR.    WO 2008/118319 relates to diphenylmethyl imidazoles with MR binding affinity for treatment of a range of conditions including cardiovascular and kidney disease.    WO 2008/53300 discloses MR antagonists for treatment of a range of conditions including cardiovascular and renal disorders.    WO 2008/126831 relates to atropisomers of N-(p-methylsulfonylphenyl)-5-(2-trifluoromethylphenyl)pyrrole-3-carboxamides as MR antagonists.    WO 2009/085584 relates to 6H-dibenzo[b,e]oxepine analogs as MR antagonists for treatment of physiological disorders like congestive heart failure, hypertension and diabetic nephropathy.    WO 2009/017190 disclose benzoxazine and chromene derivatives as MR antagonists useful as diuretics and for the prevention and/or treatment of hypertension, heart failure, myocardial infarction, angina pectoris, cardiac hypertrophy, myocardial fibrosis, vascular fibrosis, baroreceptor disorder, body fluid excess, arrhythmia, primary or secondary aldosteronism, Addison's disease, Cushing syndrome, or Bartter syndrome.    US 20100094000 relates to pyrazole derivatives as MR antagonists for use as hypertension, cardiac failure and the like.    WO 2010/098286 disclose (+)-1,4-dimethyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxam as an agent to treat diabetic nephropathy.    WO 2010/104721 relates to the specific use of 5-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-1-((7R,8aR)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-benzo[d]imidazol-2(3H)-one as a MR antagonists for prevention of diseases including congestive heart failure, diabetic nephropathy and chronic kidney disease.    WO 2010/116282 relates to dihydropyrazoles as MR antagonists for treatment of hypertension.    WO 2011/141848 relates to morpholine derivatives as MR antagonists and their use for treatment of a variety of conditions including diabetic nephropathy and endothelial dysfunction.    WO 2012/064631 discloses pyridyl ureas as antagonists of MR for treatment of e.g. heart failure.    WO 2012/008435 discloses diarylamide derivatives that inhibit MR for treatment of a range of diseases including kidney disease.    J. Med. Chem. 2011, 54, 8616 describes structure activity of benzoxazine-3-one derivatives as MR antagonists.    J. Cardiovasc. Pharmacol. 2012, 59(5), 458 describes SM-368229 as a MR antagonist with antihypertensive efficacy in rat with minimal effects on serum potassium levels.    ChemMedChem 2012, 7(8), 1385 reports the optimization of dihydropyridine to dihydronapthyridine analogs and identification of BAY 94-8862.    Mol. Cell. Endocrinol. 2012, 350, 310 reviews the pharmacology of MR antagonists and describe properties of BR-4628 and PF-3882845.    J. Med. Chem. 2012, 55, 7957 is a review in the field of non-steroidal MR antagonists.    Bioorg. Med. Chem. Lett. 2013, 23, 4388 reports on the exploration of oxazolidinone derivatives as potent MR antagonists.    Bioorg. Med. Chem. Lett. 2013, 23, 6239 reports on the exploration of arylsulfonamides as potent nonsteroidal MR antagonists.    Frontiers in pharmacology 2013, 4, 115 describe the effects of PF-03882845 in animal models of diabetic nephropathy and claim a reduced risk of hyperkalemia.    J. Med. Chem. 2014, 57(10), 4273 describe the efforts to improve nuclear hormone receptor selectivity of PF-03882845.
Despite the foregoing, there still exists a need for alternative/further improved agents for treatment of cardiovascular, inflammatory, metabolic and renal conditions, including heart failure, hypertension, chronic kidney disease, diabetic nephropathy, endothelial dysfunction, diabetes, disorders of the ocular vasculature, having, for example, the advantage that they may be more efficacious, be less toxic, be more selective, be more potent, produce fewer side effects, be more easily absorbed, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance), than compounds previously described.